The Role of CETP Modulation and Inhibition in the Progression of Coronary Heart Disease

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When you have a mortality problem and a problem with excess clinical events, certainly those arguments came to the forefront. What we’ve subsequently learned is that it really does appear that torcetrapib has a number of off-target toxicities. First of all, it has an adverse effect on blood pressure. We saw that story evolve during the development program. What we learned was that as each study progressed, the blood pressure signals seemed to become more prominent, instead of a couple of millimeters, it ended up 5–6 millimeters of mercury.

That was one problem. There were a number of problems at the level of the adrenal gland increasing aldosterone levels, increasing cortisol levels. Finally, there were some interesting studies in animals suggesting that endothelin, which we think is a potent vascular toxic factor seems to be up-regulated in the artery wall in some animal models. There seem to be a number of off-target toxicities that have got nothing to do with CETP at all.

We know that if you give torcetrapib to people, examine blood and isolate and evaluate the impact of HDL to promote cholesterol efflux in lab studies, it looks intact. That would suggest that the HDL is not dysfunctional. We went back and looked at our own imaging studies and what we found with coronary atherosclerosis in the intravascular ultrasound studies was that patients treated with torcetrapib who achieved the very highest levels of HDL-C actually regressed.

We thought that was a pretty compelling argument to suggest that the HDL was still functional. It still retained the capacity to move the lipid out of the vessel wall, and shrink the size of the plaque. We saw that on ultrasound. Putting that all together I think we’ve now got to this point where we think that there is enough to suggest that if there is another agent that we think lacks the types of toxicities of torcetrapib, then it remains a reasonable question to move forward in large outcome studies to test the hypothesis whether inhibiting CETP would be beneficial.

In 2011 there are two agents that are already in Phase III, and a third agent that is also being studied.

DR. DAVIDSON: There was evidence in ILLUMINATE7,8 as well that the higher the HDL-C in the treated group appeared to have less of a cardiovascular risk than those that did not have higher HDL-C, is that correct?

DR. NICHOLLS: Yes.

DR. DAVIDSON: Therefore the ILLUMINATE study supported the findings in the ILLUSTRATE trial that the higher the on-treatment HDL-C the greater the potential cardiovascular benefit.

DR. NICHOLLS: That’s right, and I think that one of the criticisms in the early stages of this process was the question, did the imaging miss the signals? I think that in two ways it didn’t because first of all, the only real legitimate impact we expected to see was regression of lesions. We didn’t see that at all.

When you look at these findings, it really does look that there was a potential cardiovascular benefit in patients who actually achieved the higher levels of HDL, at least suggesting that it wasn’t dysfunctional.

DR. DAVIDSON: Let’s move on to the two new CETP inhibitors that are in development and touch on the third, evacetrapib, that was recently discussed. Christie, talk about anacetrapib and the Determining the Efficacy and Tolerability of CETP Inhibition with Anacetrapib (DEFINE) trial9 and how things are moving forward with that compound for cardiovascular risk reduction.

DR. BALLANTYNE: After the first experience with torcetrapib where there were off-target effects, I think it was very important to show that the other compounds were safe. A study with anacetrapib, the DEFINE trial10 looked at the lipid effects, and reported very impressive lipid effects of raising HDL 138.1%, and reducing LDL 40%.10

There was not a problem with blood pressure as compared to torcetrapib; an aldosterone effect was not seen and there was no difference in aldosterone levels. If we looked at cardiovascular events it was also safe. If you look at the issue of revascularization there was a clearly marked reduction. If you were to have some regression of atherosclerosis one might predict that revascularization could be affected favorably.

I think that the data were sufficient; that the study met its end point of showing lipid efficacy without any evidence of harm. That the decision has been to go forth with the REVEAL study,11 which is being led by the Oxford and the Thrombolysis in Myocardial Infarction (TIMI) groups, and is now underway.

DR. DAVIDSON: Bob, please discuss dalcetrapib and the clinical trials to date in regards to its cardiovascular safety and also the outcome trials that are underway?

DR. ROSENSON: Yes, dalcetrapib has been investigated in two vascular studies that were designed to evaluate the safety of the compound. The dal-VESSEL trial12 was the multi-centered trial that evaluated blood pressure and brachial reactivity. In this study there was no change in blood pressure and no adverse change on vascular reactivity.

The dal-PLAQUE study was a trial that randomized individuals to dalcetrapib or placebo and evaluated changes in carotid plaque burden quantified by magnetic resonance imaging and vascular inflammation quantified by fluorodeoxyglucose (FDG)-positron emission tomography (PET) scanning. In this trial, treatment with dalcetrapib decreased carotid plaque burdensuggesting regression of the atherosclerosis.13

Because of the critical importance of HDL as an anti-inflammatory molecule they did evaluate vascular information by FDG-PET, but there were no overall group differences in this measure. Individuals, however, who had the greatest increase in HDL-C had the least amount of vascular inflammation. It is worth noting that dal-PLAQUE study was a relatively small study and some of the power to detect differences was limited because of the small size.

Christie was one of the authors, and maybe he wants to comment more about the dal-PLAQUE study from his perspective.

DR. BALLANTYNE: The first point was to examine with novel imaging modalities if dalcetrapib was safe, and there was not a safety concern. There was an effect in regard to total reduction of the total vessel area with dalcetrapib, which is the most accurate measure by MRI.14

However, I want to emphasize that this was a safety trial for the primary end points, and we looked at a number of secondary end points here that I think ought to be considered hypothesis generating. It was a small study. There were suggestive data that people who have worse plaque, defined by the highest uptake of deoxyglucose measured by PET/computed tomography, had the most benefit. The drug was safe in this study and the endothelial function study. The lack of any safety concerns in these studies supports the rationale for the outcomes trial, which is in progress.

DR. DAVIDSON: Steve, what is your perspective on both CETP inhibitors, because you weren’t involved with the DEFINE trial or the dal-PLAQUE or dal-VESSEL trials. How do you think these two CETP inhibitors compare? How should clinicians think about them as the larger trials start reporting?

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